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▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
archdischild-2014-306328).
1 Study design Prospective longitudinal study following
Department of Medicine,
Doherty Institute, University of
Melbourne, Parkville, Victoria,
Australia
2
Research and Training Centre
for Community Development
(RTCCD), Hanoi, Vietnam
3
Centre for Molecular,
Environmental, Genetic and
Analytic Epidemiology,
Melbourne School of
Population and Global Health,
University of Melbourne,
Parkville, Victoria, Australia
4
Provincial Centre of Preventive
Medicine, Ha Nam Province,
Vietnam
5
The Jean Hailes Research
Unit, School of Public Health
and Preventive Medicine,
Monash University, Melbourne,
Victoria, Australia
6 twofold increase in ferritin; 95% CI −78 to −5.0) were
The Victorian Infectious
Diseases Service, Royal
Melbourne Hospital, Parkville,
Victoria, Australia
Correspondence to
Dr Sarah Hanieh, Department
of Medicine, Doherty Institute,
University of Melbourne,
Parkville, Victoria 3050,
Australia;
shanieh@unimelb.edu.au
Received 3 March 2014
Revised 28 August 2014
Accepted 2 September 2014
Published Online First
22 September 2014
Open Access
Scan to access more
free content
To cite: Hanieh S, Ha TT,
De Livera AM, et al. Arch
Dis Child 2015;100:
165–173.
Antenatal and early infant predictors of postnatal
growth in rural Vietnam: a prospective cohort study
Sarah Hanieh,1 Tran T Ha,2 Alysha M De Livera,3 Julie A Simpson,3 Tran T Thuy,2
Nguyen C Khuong,4 Dang D Thoang,4 Thach D Tran,2,5 Tran Tuan,2 Jane Fisher,5
Beverley-Ann Biggs1,6
ABSTRACT
Objective To determine which antenatal and early-life
factors were associated with infant postnatal growth in a
resource-poor setting in Vietnam.
infants (n=1046) born to women who had previously
participated in a cluster randomised trial of micronutrient
supplementation (ANZCTR:12610000944033), Ha Nam
province, Vietnam. Antenatal and early infant factors
were assessed for association with the primary outcome
of infant length-for-age z scores at 6 months of age using
multivariable linear regression and structural equation
modelling.
Results Mean length-for-age z score was −0.58
(SD 0.94) and stunting prevalence was 6.4%. Using
structural equation modelling, we highlighted the role of
infant birth weight as a predictor of infant growth in the
first 6 months of life and demonstrated that maternal
body mass index (estimated coefficient of 45.6 g/kg/m2;
95% CI 34.2 to 57.1), weight gain during pregnancy
(21.4 g/kg; 95% CI 12.6 to 30.1) and maternal ferritin
concentration at 32 weeks’ gestation (−41.5 g per
indirectly associated with infant length-for-age z scores at
6 months of age via birth weight. A direct association
between 25-(OH) vitamin D concentration in late
pregnancy and infant length-for-age z scores (estimated
coefficient of −0.06 per 20 nmol/L; 95% CI −0.11 to
−0.01) was observed.
Conclusions Maternal nutritional status is an important
predictor of early infant growth. Elevated antenatal ferritin
levels were associated with suboptimal infant growth in
this setting, suggesting caution with iron supplementation
in populations with low rates of iron deficiency.
INTRODUCTION
A child’s growth and development are largely
determined by conditions experienced in utero and
during their first two years of life. Chronic under-
nutrition during this period may lead to irreversible
adverse outcomes in later life, including impaired
growth, reduced cognitive development, impaired
immune function and increased risk of chronic dis-
eases in later life, resulting in long-term conse-
quences for health and productivity in adult life.1 2
Chronic undernutrition is a major global public
health issue, and stunting (the best indicator of
chronic undernutrition) has been shown to affect
165 million children throughout the world.
Impaired growth is rarely caused by a single deter-
minant, rather it is the cumulative result of many
Hanieh S, et al. Arch Dis Child 2015;100:165–173. doi:10.1136/archdischild-2014-306328
Original article
What is already known on this topic
▸ Adverse growth outcomes within the first two
years of life may result in significant
consequences in later life.
▸ Prevalence of stunting in Asia is high, and the
key maternal and early-life factors and their
interactions leading to impaired infant growth
remain unclear.
What this study adds
▸ Maternal nutritional status plays an important
role in predicting infant growth at 6 months of
age.
▸ Elevated antenatal iron stores may be
deleterious to infant growth in this setting.
▸ Caution with antenatal iron supplementation
should be taken in populations with low rates
of iron deficiency.
different biological, cultural and socio-economic
influences occurring during the antenatal and early
infancy period. Patterns of growth faltering show
that length-for-age decreases dramatically from
birth until 24 months of age,3 and fetal growth
restriction is an important contributor to childhood
stunting.4
A recent review identified 10 key interventions
for improving maternal and child undernutrition,
including antenatal folic acid or multiple micronu-
trient (MMN) supplementation, and exclusive
breast and complementary feeding promotion.
However, modelling has shown that at 90% cover-
age, these evidence-based nutrition interventions
would only reduce stunting by 20% in children
under 5 years of age at a cost of Int$9.6 billion per
year.5 Thus, further clarification of critical maternal
and early-life factors that influence infant growth
and exploration of how these factors interact is
urgently required.
In Vietnam, stunting affects between 15% and
30% of children, with the highest incidence in chil-
dren residing in rural areas and from ethnic minor-
ity groups.6 7 Potential factors contributing to the
high rates of stunting in Vietnam may include poor
maternal health and nutrition, inadequate infant
nutrition in early life, as well as other socio-
economic and cultural influences.7
165
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Original article

Our overall objective was to determine which factors occur- model for factors impacting growth in infants residing in rural
ring during the antenatal period and first six months of life Vietnam.
were associated with infant growth (length-for-age z scores) at
6 months of age, and to clarify whether associations were direct,
METHODS
or indirectly mediated via infant birth weight. Using this infor-
Study design, setting and participants
mation, we aimed to develop a comprehensive explanatory
This prospective cohort study was conducted in Ha Nam prov-
ince in northern Vietnam between September 2010 and January
2012. Ha Nam has a population of approximately 820 100
Table 1 Baseline maternal and infant socio-economic, people, with most residents still working in subsistence agricul-
demographic, nutritional, biochemical and anthropometric factors ture. The original study protocol was approved by the
Maternal factors Values
Melbourne Health and Ha Nam Provincial Human Research
Ethics Committees. All women and infants enrolled in the ori-
Demographic factors ginal cluster randomised trial (ACTNR 12610000944033) were
Wealth index* 66.3 (0.09) eligible for enrolment in the study if length-for-age z scores
Maternal age (years)* (n=1046) 26.7 (4.9) were available at 6 months of age.
Educational level† In the original trial, women received either (1) one tablet of
Primary school 159/1046 (15.2) iron-folic acid (IFA) taken daily (60 mg elemental iron/0.4 mg
Secondary school 705/1046 (67.4) folic acid per tablet, seven tablets per week) or (2) one capsule
University/college 182/1046 (17.4) of IFA taken twice a week (60 mg elemental iron/1.5 mg folic
Occupation† acid per capsule; two capsules per week) or (3) one capsule of
Farmer/housewife 560/1046 (53.5) MMNs taken twice a week (60 mg elemental iron/1.5 mg folic
Factory worker/trader 350/1046 (33.5) acid per capsule; two capsules per week, as well as a variation of
Government official/clerk 136/1046 (13.0) the dose of the micronutrients in the United Nations
Anthropometric factors International Multiple Micronutrient Preparation supplement).8
Height (cm)* (n=1045) 153.6 (4.7) Maternal information was collected at enrolment (mean gesta-
Body mass index enrolment (kg/m2)* 19.9 (2.0) tional age 12.2 weeks) and 32 weeks gestation, and infant
Body mass index group enrolment†
Underweight (<18.5 kg/m2) 271/1045 (25.9)
Normal (18.5–25 kg/m2) 759/1045 (72.6) Table 2 Baseline infant nutritional, biochemical and
Overweight (>25 kg/m2) 15/1045 (1.4) anthropometric factors
Mid upper arm circumference enrolment (cm)* (n=1045) 23.8 (2.1)
Infant factors Values
Weight gain during pregnancy (kg)* (n=958) 8.19 (2.6)
Antenatal factors Demographic factors
Gravidity† Male sex* 557/1045 (53.3)
Primigravida 326/1046 (31.2) Neonatal outcomes
Multigravida 720/1046 (68.8) Birth weight (g)† 3155 (393.7)
Type of supplement taken during pregnancy† Birth length (cm)† 49.2 (2.9)
Daily IFA supplements 350/1046 (33.5) Birth head circumference (cm)† 32.7 (2.1)
Twice weekly IFA supplements 363/1046 (34.7) Gestational age at delivery (weeks)† 39.1 (2.0)
MMN supplements 333/1046 (31.8) 6-week outcomes
Change of diet when pregnant† Infant weight (g)† 3154 (396.0)
No 259/1046 (24.8) Infant length (cm)† 56.5 (3.7)
Yes 787/1046 (75.2) Infant head circumference (cm)† 37.4 (2.1)
Meat intake during pregnancy at enrolment (number of 3.85 (2.26) Dietary factors
times per week)* (n=1046)
Continued breast feeding at 6 months of age* 1045/1046 (99.9)
Persistent depression EPDS†
Exclusively breast fed at 6 months of age* 191/1045 (18.3)
No 909/1046 (94.9)
First introduction of complementary food (weeks)† 17.2 (4.01)
Yes 49/1046 (5.1)
Infant morbidity 6 weeks
Biochemical factors
Infant diarrhoea* 48/1038 (4.6)
Haemoglobin enrolment (g/dL)* (n=1046) 12.3 (1.2)
Infant cough* 123/1038 (11.9)
Haemoglobin 32 weeks (g/dL)* (n=948) 12.4 (1.2)
Infant fever* 12/1038 (1.2)
Ferritin enrolment (μg/L)‡ (n=1042) 77 (50 to 127)
Infant hospitalisation* 75/1038 (7.2)
Ferritin 32 weeks (μg/L)‡ (n=945) 28 (17 to 42)
Infant morbidity 6 months
Iodine (μg/L)‡ (n=954) 53 (30.6 to 87.3)
Infant diarrhoea* 421/1046 (40.3)
B12 enrolment‡ (pmol/L) (n=1043) 394 (317 to 499)
Infant cough* 593/1046 (56.7)
B12 at 32 weeks‡ (pmol/L) (n=945) 232 (187 to 285)
Infant fever* 265/1046 (25.3)
Folate enrolment‡ (nmol/L) (n=1041) 28 (21.6 to 34.4)
Infant hospitalisation* 213/1046 (20.4)
Folate at 32 weeks‡ (nmol/L) (n=944) 28.7 (22.4 to 33.5)
Biochemical factors
25-(OH) vitamin D* (nmol/L) (n=891) 70.6 (22.2)
Infant haemoglobin (g/dL)† 11.0 (1.1)
*Values are mean (SD). Infant ferritin (μg/L)‡ 31 (17 to 53)
†Values are number (%).
‡Values are median (25th–75th percentile). *Values are number (%).
IFA, iron-folic acid; MMN, multiple micronutrient; EPDS, Edinburgh Postnatal †Values are mean (SD).
Depression Scale. ‡Values are median (25th–75th percentile).

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Figure 1 Study flow diagram.

anthropometric measurements were performed at birth, 6 weeks
and 6 months of age. Detailed information on the methodology
used, including a table describing the composition of the supple-
ments, has been previously published.9
The wealth index was used to measure the socio-economic
status of the household and was constructed from three compo-
nent indices: housing quality (four items, response 0 or 1), con-
sumer durables (nine items, response 0 or 1) and services (four
items, response 0 or 1). A simple average of these three compo-
nents was calculated to produce a value between 0 and 1 (scale
from poorest to better-off ).10
Infant crown-heel length was measured using a portable
Shorr Board (Shorr productions, Olney, Maryland, USA). Infant
length-for-age z scores were calculated using WHO Anthro
Hanieh S, et al. Arch Dis Child 2015;100:165–173. doi:10.1136/archdischild-2014-306328
(V.3.2.2, January 2011).11 Stunting was defined as
length-for-age z scores <2 SDs below WHO Child Growth
Standards.12
Statistical methods
Data were analysed using Stata, V.12 (StataCorp, College
Station, Texas, USA). Categorical data are presented as percen-
tages with frequency, and continuous data are presented as
mean and SD. Data found to be skewed were presented as the
median with IQRs (25th –75th centile) and log transformed for
the regression analyses. The assumption of a linear association
between continuous exposure measures and infant height for
age z scores was tested by comparing regression models with
categorical (quartile groupings) and pseudo-continuous variables
167
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Original article

by likelihood ratio tests. Variables that had no evidence for non-
linearity of associations were used as continuous variables. In
order to enhance clinical interpretability, maternal ferritin con-
centration was also categorised into four quartiles (lowest to
highest). We tested for exposure–outcome associations that may
have been modified by the trial intervention arm (exposures:
ferritin, folate, B12, vitamin D and iodine concentration) using
interaction terms and the likelihood ratio test, and found no evi-
dence of interaction.
The rationale for using a structural equation model was based
on the hypothesis that maternal and early infant factors have a
complex and inter-related influence on early infant growth. We
initially constructed a hypothesised causal diagram for how
these factors and infant length-for-age z scores may be con-
nected. Following this, univariable and multivariable linear
regression was performed to examine the association between
maternal (early and late) and early infant factors that predicted
infant birth weight and length-for-age z scores at 6 months of
age. Separate multivariable linear regression models for mater-
nal and early infant factors were developed using backward
elimination stepwise regression as a way of selecting a subset of
variables that were statistically significantly associated with
infant birth weight and length-for-age z scores. The models
obtained this way were then improved by including/excluding
variables with borderline p values, clinically important con-
founding factors identified a priori from the literature and those
that had statistically significant associations with length-for-age z
scores at 6 months of age in the univariable analysis. Proceeding
this way, the optimal models were selected with the aid of likeli-
hood ratio tests and adjusted R2 values.13
Using the results of the univariable and multivariable regres-
sion analysis, the structural equation model was built and
iteratively tested. The fit of the model was tested using the χ2
test comparing the fitted model with a saturated model, com-
parative fit index (CFI) comparing the fitted model with a base-
line model, which assumes that there is no relationship among
the variables, and root mean squared error of approximation
(RMSEA) that penalises the model for excessive complexity.13 14
A good model should have an insignificant p value for the
χ2 test (≥0.05), CFI close to one (≥0.95) and low RMSEA
(≤0.05).13 14
RESULTS
At 6 months of age visit, length-for-age z scores were available
on 1046 infants. Baseline maternal and infant socio-economic,
demographic, nutritional, biochemical, anthropometric and
morbidity outcomes are presented in tables 1 and 2. There were
no clinically significantly differences in baseline characteristics
between infants with available length for age z scores and those
in whom measurements were unavailable (see online
supplementary table S1). Mean length-for-age z score at
6 months of age was −0.58 (SD 0.94), and prevalence of

Table 3 Associations between maternal factors in early pregnancy and infant length-for-age z scores at 6 months of age (univariable and
multivariable regression)
Univariable regression Multivariable regression*

Maternal factors Coefficient (95% CI) p Value Coefficient (95% CI) p Value

Demographic factors
Maternal age (years) 0.01 (−0.01 to 0.02) 0.18
Education
Primary school Reference
Secondary school 0.05 (−0.11 to 0.21) 0.55 0.04 (−0.12 to 0.20) 0.63
University 0.23 (0.03 to 0.43) 0.03 0.18 (−0.12 to 0.20) 0.07
Gravidity
Primgravida Reference –
Multigravida 0.01 (−0.12 to 0.13) 0.93
Nutritional and health status
Height (per 5 cm) 0.25 (0.20 to 0.35) <0.001 0.25 (0.20 to 0.35) <0.001
Body mass index at enrolment (kg/m2) 0.03 (0.01 to 0.06) 0.02 0.04 (0.01 to 0.07) 0.01
Mid upper arm circumference enrolment(cm) 0.04 (0.01 to 0.07) 0.01
Depression on enrolment (EPDS)
No Reference –
Yes −0.12 (−0.26 to 0.03) 0.11
Antenatal practices
Change of diet when pregnant
No Reference –
Yes 0.02 (−0.11 to 0.15) 0.74
Meat intake during pregnancy at enrolment (number of times per week) 0.01 (−0.02 to 0.03) 0.47
Use of traditional supplements during pregnancy −0.21 (−0.30 to 0.26) 0.88
Micronutrient status
Haemoglobin enrolment (per 10 g/dL) −0.10 (−0.60 to 0.40) 0.63
Ferritin enrolment (log2 μg/L)† −0.04 (−0.12 to 0.04) 0.33
B12 enrolment (log2 pmol/L)† 0.01 (−0.16 to 0.16) 0.99
Folate enrolment (log2 nmol/L)† 0.13 (−0.01 to 0.27) 0.07
*Model adjusted for maternal age, gravidity, gestational age at enrolment and trial intervention.
†Log2 transformed—regression coefficient represents mean change in infant length-for-age z score associated with a twofold change in ferritin, B12 or folate.
EPDS, Edinburgh Postnatal Depression Scale.

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stunting at 6 months of age was 6.4% (95% CI 5.0% to 7.9%). women with serum ferritin concentrations in the highest quar-
Prevalence of underweight was 3.3% (95% CI 2.2% to 4.4%) tile (43–273 μg/L) compared with those born to women with
and wasting was 1.6% (95% CI 0.71% to 2.16%). A flow ferritin concentrations in the lowest quartile (4–17 μg/L) (esti-
diagram of the study is presented in figure 1. mated coefficient −106.4 g, 95% CI −174.9 to −38.0).

Univariable analyses Early infant factors

The results are presented in tables 3–5.
Multivariable analyses
The results of adjusted models are presented in tables 3–5.
Maternal factors
Maternal body mass index (BMI) at enrolment (estimated coeffi-
cient 0.04/kg/m2, 95% CI 0.01 to 0.07) and weight gain during
pregnancy (0.04/kg, 95% CI 0.01 to 0.06) were positively asso-
ciated with infant length-for-age z scores at 6 months of age.
There was an inverse association with 25-(OH) vitamin D con-
centration in late pregnancy (−0.06 per 20 nmol/L, 95% CI
−0.11 to −0.001). No association between maternal iodine and
infant length-for-age z scores was demonstrated (estimated coef-
ficient −0.02 per twofold increase in iodine, 95% CI −0.09 to
0.05).
Maternal risk factors associated with infant birth weight are
presented in online supplementary tables S2 and S3. Maternal
haemoglobin (estimated coefficient of −268 g per 10 g/dL, 95%
CI −459 to −76) and ferritin (−66.7 g per twofold increase
in ferritin, 95% CI −104.1 to −29.2) levels at 32 weeks gesta-
tion were inversely associated with infant birth weight. Mean
birth weight was significantly lower in infants born to
Birth weight (estimated coefficient of 0.10 per 100 g increase in
birth weight, 95% CI 0.09 to 0.12), gestational age at birth
(0.04 per 1 week increase in gestational age, 95% CI 0.01 to
0.07) and use of dietary supplements in the child (0.25, 95% CI
0.07 to 0.43) were positively associated with infant
length-for-age z scores at 6 months of age. Infant sex (males vs
females; −0.31, 95% CI −0.43 to −0.20), infant ferritin con-
centration (−0.19 per twofold increase in ferritin, 95% CI
−0.25 to −0.12) and hospitalisation within the first six months
of life (−0.22, 95% CI −0.41 to −0.04) were found to be
inversely associated with length-for-age z scores at 6 months
of age.
Structural equation model
A structural equation model predicting infant length-for-age z
scores is shown in figure 2 and table 6. This model presents a
theoretical causal path between maternal socio-economic
factors, nutritional and micronutrient status during pregnancy
and highlights the role of infant birth weight as a predictor of
infant growth in the first six months of life. The model demon-
strates that maternal BMI, weight gain during pregnancy, gesta-
tional age at delivery and maternal ferritin concentration at
32 weeks gestation were indirectly associated with length-for-age

Table 4 Associations between maternal factors in late pregnancy and infant length-for-age z scores at 6 months of age (univariable and
multivariable regression)
Univariable regression Multivariable regression*

Maternal factors in late pregnancy Coefficient (95% CI) p Value Coefficient (95% CI) p Value

Nutritional and health status

Body mass index (kg/m2) at 32 weeks gestation 0.06 (0.03 to 0.09) <0.001 0.04 (0.01 to 0.07) 0.01
Weight gain during pregnancy (kg) 0.05 (0.03 to 0.07) <0.001 0.04 (0.01 to 0.06) 0.004
Depression at 32 weeks’ gestation (EPDS)
No Reference –
Yes −0.03 (−0.21 to 0.15) 0.75
Persistent depression (enrolment and 32 weeks) (EPDS)
No Reference –
Yes −0.22 (−0.49 to 0.04) 0.10
Change of diet at 32 weeks gestation
No Reference –
Yes −0.04 (−0.18 to 0.11) 0.63
Meat intake during pregnancy at 32 weeks gestation (no. times per week) −0.01 (−0.04 to 0.02) 0.54
Use of traditional supplements during pregnancy
No Reference –
Yes −0.25 (−0.70 to 0.21) 0.29
Micronutrient status at 32 weeks
Haemoglobin (per 10 g/dL) −0.30 (−0.80 to 0.20) 0.25
Ferritin (log2 μg/L)† −0.07 (−0.17 to 0.02) 0.11
B12 (log2 pmol/L)† −0.16 (−0.34 to 0.02) 0.08
Folate (log2 nmo/L)† −0.03 (−0.19 to 0.12) 0.69
Vitamin D (per 20 nmol/L) −0.07 (−0.12 to −0.01) 0.02 −0.06 (−0.11 to −0.001) 0.04
Urinary iodine (log2 μg/L)† −0.02 (−0.09 to 0.05) 0.56
*Model adjusted for maternal age, gravidity, gestational age at enrolment, infant sex and trial intervention.
†log2 transformed—regression coefficient represents mean change in infant length-for-age z score associated with a twofold change in ferritin, B12, folate or iodine.
EPDS, Edinburgh Postnatal Depression Scale.

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Table 5 Associations between early infant factors and infant length-for-age z scores at 6 months of age (univariable and multivariable
regression)
Univariable regression Multivariable regression*

Early infant factors Coefficient (95% CI) p Value Coefficient (95% CI) p Value

Neonatal factors
Birth weight (per 100 g) 0.09 (0.07 to 0.10) <0.001 0.10 (0.09 to 0.12) <0.001
Gestational age at delivery (weeks) 0.11 (0.08 to 0.14) <0.001 0.04 (0.01 to 0.07) 0.02
Male sex −0.19 (−0.31 to −0.08) 0.001 −0.31 (−0.43 to −0.20) <0.001
Six-week anthropometric measurements†
Infant length (cm) 0.09 (0.08 to 0.11) <0.001 0.09 (0.08 to 0.11) <0.001
Infant weight (kg) 0.90 (0.77 to 1.03) <0.001
Infant head circumference 0.07 (0.04 to 0.10) <0.001
Infant health status 6 weeks of age†
Respiratory illness −0.22 (−0.40 to −0.04) 0.02 −0.20 (−0.38 to −0.02) 0.02
Fever −0.35 (−0.89 to 0.18) 0.20
Diarrhoea 0.03 (−0.25 to 0.30) 0.85
Hospitalisation −0.40 (−0.62 to −0.18) <0.001 −0.25 (−0.47 to −0.03) 0.03
Infant health status 6 months of age
Respiratory illness −0.10 (−0.21 to 0.02) 0.10
Fever −0.22 (−0.35 to −0.09) 0.001
Diarrhoea −0.05 (−0.17 to 0.07) 0.39
Hospitalisation −0.28 (−0.42 to −0.14) <0.001 −0.22 (−0.41 to −0.04) 0.02
Child care practices
Exclusive breast feeding at 6 weeks of age 0.03 (−0.09 to 0.15) 0.60
Exclusive breast feeding at 6 months of age −0.08 (−0.23 to 0.06) 0.26
Timing of introduction of complementary food (weeks) 0.01 (−0.009 to 0.03) 0.07
Use of formula at 6 weeks of age −0.03 (−0.15 to 0.09) 0.62
Use of formula at 6 months of age −0.11 (−0.30 to 0.08) 0.27
Use of dietary supplements for child in the first 6 months 0.29 (0.11 to 0.47) 0.001 0.25 (0.07 to 0.43) 0.01
Micronutrient status at 6 months of age
Haemoglobin (per 10 g/dL) 0.10 (−0.40 to 0.60) 0.75
Ferritin (log2 μg/L)‡ −0.08 (−0.15 to −0.01) 0.02 −0.19 (−0.25 to −0.12) <0.001
*Model adjusted for maternal age, gravidity, gestational age at enrolment and trial intervention.
†Variables at the 6 -week time point have been included in separate multivariable regression models as they are on the causal pathway between birth weight and length-for-age z
scores at 6 months of age.
‡log2 transformed—regression coefficient represents mean change in infant length-for-age z score associated with a twofold change in ferritin.

z scores via infant birth weight, whereas there was a direct asso-
ciation with maternal height, 25-(OH) vitamin D concentration
in late pregnancy, infant sex and hospitalisation in the first six
months of life. The model fits the data well (χ2 p value 0.16,
CFI=0.990, RMSEA=0.02 with 0.96 probability of RMSEA
being ≤0.05).
DISCUSSION
To our knowledge, this is the largest study to present a compre-
hensive overview of maternal and early infant predictive factors
for infant growth in Southeast Asia. Using structural equation
modelling, we were able to identify factors that were directly
associated with infant length-for-age z scores at 6 months of age
and those that were indirectly associated through infant birth
weight. Significantly, we found that maternal antenatal ferritin
levels were inversely associated with infant growth at 6 months
of age and that this was mediated through infant birth weight.
Physiologically normal maternal iron status has been shown
to play an important role in reducing the risk of preterm deliv-
ery and low-birthweight infants.15 However, recent findings
indicate that adverse pregnancy outcomes may also occur in
association with high haemoglobin and serum ferritin concen-
trations, including fetal growth restriction, preterm delivery, low
birth weight and pre-eclampsia.16 This may be explained by
170
increased oxidative stress, failure of expansion of the maternal
plasma volume or increased risk of intrauterine infection.17–20
Our finding that higher late gestational ferritin stores were indir-
ectly associated with reduced length-for-age Z scores at
6 months of age through birth weight extend those of Lao
et al,21 who demonstrated an inverse association between serum
ferritin and infant birth weight in an observational study of 488
pregnant women with baseline haemoglobin ≥10 g/dL.
We also found a negative association between infant ferritin
and length-for-age z scores. Although a recent meta-analysis
concluded that infant iron supplementation had no effect on
growth,22 several studies have documented a negative impact on
the linear growth of children during or following iron supple-
mentation.23 24 Our findings require further exploration and
highlight the need for caution in administrating daily iron to
non-anaemic pregnant women and infants who already have
sufficient iron stores. This is particularly important in many
countries where rapid economic development has been asso-
ciated with a reduction in the prevalence of anaemia and iron
deficiency in pregnant women.25
We observed an inverse relationship between length-for-age z
scores at 6 months of age and maternal 25-(OH) vitamin D,
although the estimated magnitude of change associated with an
increase in 25-(OH) vitamin D of 20 nmol/L was small (−0.06
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Original article

Figure 2 Structural equation model of factors occurring during pregnancy and early infancy influencing infants’ length-for-age z scores at
6 months of age. All of the variables in the diagram are observed. Single-headed solid arrows represent statistically significant directional paths at a
significance level of 0.05. Dotted lines indicate hypothesised but non-significant paths. Path coefficients are linear regression coefficients and 95%
CIs representing the variables with direct relationships with infant birth weight or length-for-age z scores at 6 months of age.

per 20 nmol/L).26 Leffelaar et al27 demonstrated accelerated
growth in length during an infant’s first year of life in infants
born to mothers with 25-(OH) vitamin D <30 nmol/L and pos-
tulated that this may be due to increasing 25-(OH) vitamin D
levels postnatally either through micronutrient supplementation
or fortified bottle feeds. Other studies have shown no differ-
ences in weight or height across quartiles of 25-(OH) vitamin D
status during infancy.28 29
The positive association between BMI/gestational weight gain
and infant growth is likely to be due to restricted intrauterine
blood flow leading to reduced uterine and placental growth,
and increased risk of intrauterine growth retardation and low
birth weight,30–32 both of which have been shown to be import-
ant contributors to stunting in childhood.4 We also found that
hospitalisation had a negative effect on early infant growth. In
addition to the adverse effects of disease, hospitalisation may
interfere with a mother’s ability to breast feed or provide other
care-giving practices.4
Strengths of our study include the large sample size, rigorous
trial design of the original cluster randomised controlled trial
and use of structural equation modelling to determine whether
variables were directly or indirectly associated with infant
growth. Our study was conducted in a rapidly developing rural
area, representative of many areas of Vietnam, and thus our
findings are likely to be generalisable to other parts of the
country. Although our study was set in the context of a clinical
trial of micronutrient supplementation, we found no evidence
for modification of associations by trial intervention arm. A
limitation of studying predictors of growth within a clinical trial
context is that participants in a trial may not be representative
of the rest of the population. Other limitations of the study
were that the volume of blood that could be acceptably col-
lected from infants was limited, leading to only 88% of infants
with infant ferritin results at 6 months of age. As well, the
passive method used to collect information on infant illness and
hospitalisation may have introduced recall bias, although it is
likely that mothers would have been able to recall periods of
hospitalisation.
There is mounting evidence that fetal undernutrition in
middle-to-late gestation leads to disproportionate fetal growth
and persisting changes in blood pressure, cholesterol metabol-
ism, insulin responses to glucose and other metabolic para-
meters, resulting in the programming of chronic diseases such as
hypertension, coronary heart disease and high cholesterol, later
in life.33–35 The pathways identified in this study will assist with
appropriate targeting of future maternal and infant interventions
and provide a framework to inform policy measures for early
prevention of chronic undernutrition in children in rural
Vietnam.
CONCLUSION
Maternal nutritional status is an important predictor of early
infant growth. Our finding of a potential deleterious effect of
higher maternal and infant iron stores on infant growth requires
further exploration and suggests a cautious approach to iron
supplementation during the antenatal and early infancy periods
in populations with low rates of iron deficiency. Future research
should also explore the role of maternal 25-(OH) vitamin D in
child growth and development.

Hanieh S, et al. Arch Dis Child 2015;100:165–173. doi:10.1136/archdischild-2014-306328 171

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Original article

Table 6 Structural equation model for maternal (early and late pregnancy) and infant factors associated with infant length-for-age z scores at
6 months of age
Indirectly associated with infant length-for-age z scores through birth weight (g) Coefficient (95% CI)* p Value

Maternal factors
Demographic factors
Gravidity
Primigravida Reference
Multigravida 124.8 (76.0 to 173.5) <0.001
Nutritional and health status
Height at enrolment (per 5 cm) 68.5 (44 to 93) <0.001
Body mass index at enrolment (kg/m2) 45.6 (34.2 to 57.1) <0.001
Gestational weight gain (kg) 21.4 (12.6 to 30.1) <0.001
Micronutrient factors
Ferritin at 32 weeks (log2 μg/L)† −41.5 (−78.0 to −5.0) 0.03
Infant factors
Male sex 65.6 (21.1 to 110.1) 0.004
Gestational age at delivery (weeks) 58.8 (46.1 to 71.4) <0.001

Directly associated with infant length-for-age z scores Coefficient (95% CI)‡ p Value

Maternal factors
Demographic factors
Wealth index 0.66 (0.01 to 1.31) 0.05
Nutritional factors
Height at enrolment (cm) 0.04 (0.03 to 0.06) <0.001
Micronutrient factors
Vitamin D at 32 weeks (per 20 nmol/L) −0.06 (−0.11 to −0.01) 0.03
Infant factors
Birth weight (per 100 g) 0.07 (0.05 to 0.09) <0.001
Infant hospitalisation −0.17 (−0.31 to −0.03) 0.02
Male sex −0.20 (−0.32 to −0.09) <0.001
*Regression coefficient represents estimated mean change in birth weight (g) associated with the maternal or infant factor (note for ferritin this is for a twofold increase in ferritin
levels).
†log2 transformed—regression coefficient represents mean change in infant birth weight associated with a twofold change in ferritin.
‡Regression coefficient represents estimated mean change in length-for-age z score associated with the maternal or infant factor.

Acknowledgements We thank the participants and health workers in Ha Nam REFERENCES

Province; the Ha Nam Provincial Centre of Preventive Medicine; the Viet Nam Ministry
of Health; Research and Training Centre for Community Development (RTCCD); and
those involved in the original cluster randomised trial study design9; Beth Hilton-Thorp
(LLB) and Christalla Hajisava for Departmental support; and Alfred Pathology.
Contributors SH, B-AB, JF and TT conceived the study idea and designed the
study. TTH, NCK and DDT coordinated and supervised data collection at all sites.
SH, TTH and TDT designed the data collection instruments. TTH, TTT and NCK
collected the data. SH reviewed the literature. JAS directed the analyses, which were
carried out by SH and AMdL. All authors participated in the discussion and
interpretation of the results. SH organised the writing and wrote the initial drafts. All
authors critically revised the manuscript for intellectual content and approved the
final version.
Funding The original cluster randomised trial was funded by a grant from the
Australian National Health and Medical Research Council (grant number 628751).
Competing interests None.
Ethics approval Melbourne Health Human Research Ethics Committee, and the
HaNam Provincial Human Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data from the study would be available if authors are
contacted subject to agreements within the ethical approvals for the study.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
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and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
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Antenatal and early infant predictors of

postnatal growth in rural Vietnam: a
prospective cohort study
Sarah Hanieh, Tran T Ha, Alysha M De Livera, Julie A Simpson, Tran T
Thuy, Nguyen C Khuong, Dang D Thoang, Thach D Tran, Tran Tuan,
Jane Fisher and Beverley-Ann Biggs

Arch Dis Child 2015 100: 165-173 originally published online September
22, 2014
doi: 10.1136/archdischild-2014-306328

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